High levels of adipose tissue define obesity and are strongly correlated to non-insulin dependent diabetes mellitus. Tumor necrosis factor-alpha (TNF-alpha) is expressed in adipose tissue and is thought to regulate adipose mass. The hypothesis underlying this proposal is that adipose tissue mass can be controlled by sustained local delivery of adiporegulatory compounds. The specific aims of this proposal are: 1) Develop biodegradable, injectable polymer systems capable of the sustained delivery of TNF-alpha protein and TNF-alpha antisense RNA for 1 week, 1-2 months, and over 4 months; 2) Establish and characterize an obese rat model to provide functional adipose tissue for regulation in vivo; 3) Define the regulation of the body mass index, adipocyte size and number, and apoptosis by local delivery of TNF-alpha protein and TNF- alpha antisense RNA in vivo. By investigating the role of TNF-alpha in regulating adipose tissue mass and its pathological effects linked to NIDDM, the goal is to gain insight into the mechanisms of adipose tissue biology and its relationship to NIDDM that could lead to novel approaches to treating devastating metabolic pathologies associated with obesity.